Reaction mass of aluminium chloride, iron dichloride, magnesium chloride and manganese dichloride

Endpoint summary

Description of key information

oral: STOT RE 1 (not yet finally assessed as based on secondary source data)

dermal: data not sufficient, STOT RE1 based on the oral assessment (not yet finally assessed as based on secondary source data)

inhalation: not relevant as the liquid form does not produce inhalable particles

Additional information

The test substance is a watery solution of metal chlorides and free hydrogenchloride.

The toxicity of this mixture has therefore to be regarded as a summary of the toxicity of the different ingredients. Due to the relative concentrations for repeated dose toxicity FeCl2, MnCl2, AlCl3 and HCl are regarded. MgCl2 the only other substance of high concentration is disregarded due to the low overall toxicity of this substance and as both chloride and magnesium ions are essential for cellular life and present in every cell in high abundance.

Summary:

. Calculations are based on the following composition:

	% (w/w) in solution	MW (Metal) g/mol	M = mol/L	mol % Metal		MW (compound) g/mol	% (w/w) in solution	% (w/w) dry substance
Fe	9.5224	55.85	1.7050	62.7	FeCl2	126.75	21.60	63.18
Al	0.6813	26.98	0.2525	9.3	AlCl3	133.34	3.38	9.881
Mg	0.6497	24.30	0.2674	9.8	MgCl2	95.22	2.61	7.634
Mn	1.4832	54.94	0.2700	9.9	MnCl2	125.84	3.40	9.945
					HCl	36.46	1.3	3.80
Ni	0.0080	58.69	0.0014	0.1	NiCl2	129.60	0.0176	0.0515

 

- oral:

FeCl2:

The guidance level pupblished by EVM is based on human data and therefore more relevant than animal data. Nevertheless for its derivation an interspecies factor of 3 is instead of 10 as proposed in the Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health.

Therefore the value proposed by EVM is devided by 3.33 and corrected to represent FeCl2:

DNEL-equivalent(chronic) for FeCl2: 0.19 mg/kg bw/d

MnCl2:

The DNEL equivalent for MnCl2 is based on human data and published as Tolerable Upper Intake Level established by the U.S. Food and Nutrition Board/Institute of Medicine:

DNEL-equivalent(chronic) for MnCl2: 0.16 mg manganese/kg/d

AlCl3:

The most critical value is reported from adevelopmental neurotoxicity study, reporting NOAEL of 30 mg/Kg bw Al(III) (= 148.27 mg/kg bw/d AlCl3).

Following a conservative approach subchronic exposure is assumed (assessment factor of 2) and the following standard factors are used:inter species (rat -> human: 2.5), allometric scaling (rat to human: 4.0), intra species (workers: 5.000).

Based on this assumptions the following DNEL is calculated:

DNEL(chronic): 1.483 mg/kg bw/d

HCl:

Not relevant for oral exposure.

The three ingredients that trigger oral toxicity have comparable molecular masses (FeCl2: 126.75 g/mol, MnCl2: 125.84 mg/mol, AlCl3: 133.34 g/mol). Therefore the derived DNELs can directly be compared.

DNELs for FeCl2 and MnCl2 (which make up for 73 % (w/w) of the dry mass of the test substance) are about an order of magnitude below AlCl3. Potentiation of effects is rather unlikely as for FeCl2 the liver and the hematopoietic system are the most sensitive targets, while neurotoxicity is relevant for MnCl2.

As a conservative approach, the DNEL of 0.16 mg/kg bw/d for MnCl2 is extrapolated for the total dry mass of the test substance which represents 34.19 % (w/w) of the total solution.

 

The chronic oral DNEL for the test substance is 0.16 mg/kg bw/d / 0.3419 = 0.47 mg/kg bw

 

- dermal:

There is not sufficient experimental data available to determine a dermal DNEL.

Following a conservative approach the oral DNELs are used as approximation for dermal DNELs, assuming comparable absorption.

 

The chronic dermal DNEL for the test substance is 0.16 mg/kg bw/d / 0.3419 = 0.47 mg/kg bw

 

(The chronic dermal DNEL for test substance regarding the dry mass is 0.16 mg/kg bw/d)

 

- inhalation:

FeCl2:

There is no reliable data available. As a conservative DNEL is based on MnCl2, the potential risk by the inhalation of FeCl2 as ingredient of the test substance is expected to be covered sufficiently.

MnCl2:

The TLV–TWA of 0.02 mg Mn/m³ for respirable particulate matter can be used as surrogate for a DNEL as it is derived based on human data.

AlCl3:

The LOAEC of 17.76 mg/m³ as derived from the key study serves as start value for the derivation of a DNEL. The following standard assessment factors are used: exposure duration (6 h -> 8 h: 1.5), breathing volume correction (normal breathing to light work: 1.5), inter species (rat -> human: 2.5), intra species (workers: 5.0), study duration (subchronic to chronic: 2.0), starting point (LOAEC: 3.0)

Thereby a DNEL(chronic) of 0.105 mg/m³ can be calculated.

HCl:

A NOAEC of 30 mg/m³ is found in the key study and serves as start value for the derivation of a DNEL. The following standard assessment factors are used: exposure duration (6 h -> 8 h: 1.5), breathing volume correction (normal breathing to light work: 1.5), inter species (rat -> human: 1.0 for local effects), intra species (workers: 5.0), study duration (subchronic to chronic: 2.0), starting point (NOAEC: 1.0)

Thereby a DNEL(chronic) of 0.444 mg/m³ can be calculated.

 

MnCl2 has clearly the lowest DNEL and thereby drives the DNEL derivation for the test substance. As MnCl2 has concentrations of 3.4 % (w/w) of the total mixture and 9.945 % (w/w) of the dry mass the following DNELs apply:

 

The chronic inhalation DNEL for the test substance is 0.02 mg/kg bw/d / 0.034 = 0.59 mg/m³

 

(The chronic inhalation DNEL for the test substance regarding the dry mass is 0.2 mg/m³)

 

 

The summary is based on the data presented below

- oral:

FeCl2:

For FeCl2 Choi 2004 A is the key study, an OECD TG 422 compliant study on ferrous chloride where animals were dosed up to 49 days. Dose levels of 0, 125, 250 and 500 mg/kg bw/day were administered to animals of both sexes for 42 days (males) and 42-54 days (females) using oral gavage. Clinical signs such as blackish stool and salivation were observed during the test period, but these were recovered within the recovery period. While all male rats survived, there were three female deaths in the 500 mg/kg bw/day group only. The cause of death was gastrointestinal damages by the test substance. Water consumption was increased in animals of both sexes from the 500 mg/kg bw/day groups. The rate of body weight gain showed a statistically significant decrease in males of the 250 and 500 mg/kg bw/day groups. For female rats, no dose-related change was observed. Body weight gain was reduced in males by 21% in the 250 mg/kg group and by 37% in the 500 mg/kg group, and in females by 17% in the 250 and by 15% in the 500 mg/kg groups. The sensory reactivity, the auricle reflex and corneal reflex tests, in male and female tested groups were not different from control groups. Urinalysis showed no difference between control and treated groups. Haematologically, mean cell volume (MCV) was increased by 7% in the 500 mg/kg bw/day male treatment group, and methaemoglobin (MetHB) decreased by up to 78% for females in the 125, 250 and 500 mg/kg bw/day treatment groups. Cases of diffuse black colored liver and hemorrhage with diffuse black pigmentation in necropsy opinion were caused by the test substance in males of the 500 mg/kg bw/day group, but these were recovered during the recovery period. Blood chemistry analyses revealed that cholinesterase was decreased in males by up to 41% at doses of 250 and 500 mg/kg bw/day. Statistically significant differences were found in mean cell volumes (MCV), eosinophils (EOS), platelets (PLT), cholinesterase (CS), and triglycerides (TG). But these were within the biologically normal range and there were no dose-dependent changes. Organ weight measurements showed that liver weights were increased by up to 24% absolute weight in intermediate and high dose animals of both sexes, with adrenal weights increased by up to 31% absolute weight, 61% relative weight in males and thymus weights decreased by up to 32% absolute weight, 27% relative weight in females from these same treatment groups (relative and absolute values altered in all instances). Histopathological examination showed hemosiderin deposits in the hepatocytes, hyperplasia of the adrenals and zona fasciculata, hyperkeratosis of forestomach, hemosiderin deposits in the stomach, and neutrophil infiltration of submusoca in both sexes of the animals, at 500 mg/kg bw/day. In the case of decedent animals, severe villous atrophy of forestomach was observed; abnormalities of gastric function were detected. Therefore, it is concluded that deaths in female rats were caused by physical irritancy of the test substance. The NOAEL was concluded to be 125 mg/kg bw/day for males and females, equivalent to 55 mg Fe/kg bw/day. This NOAEL is based on changes in body weight gain, liver and adrenal weight, MCV and cholinesterase in males, and changes in body weight gain, liver and thymus weight and MetHB in females.

In addition to the key study there is an oral 13-week dose-range finding study on ferric chloride (Sato 1992), with a reliability of 2. The NOAEL was 0.5% (equivalent to 277 and 314 mg/kg bw/day in males and females, respectively, and 57 and 65 mg Fe/kg bw/day, respectively) based on the reduced body weight gain. As this study has a longer exposure duration and reports a comparable the result is not in contradiction to the the key study.

Human data:

A Guidance Level is published by EVM (2003, see section 7.10.3) . In their evaluation effects of oral iron intake they come to the following conclusion:

“For guidance purposes, a supplemental intake of approximately 17 mg/day (equivalent to 0.28 mg/kg bw/day for a 60 kg adult) would not be expected to produce adverse effects in the majority of people. This is derived by dividing the lower end of the range found to have an effect by an uncertainty factor of 3 to allow for extrapolation from a LOAEL to a NOAEL. This is based on data referring to ferrous iron (Fe II), which is the form of iron used in supplements currently available in this country. No additional uncertainty factor is needed for inter-individual variation because the assessment is based on studies on large numbers of people. A safe upper level for total iron has not been estimated, as gastrointestinal effects are associated with iron in supplements rather than in foods.”

This value is valid for healthy persons and excludes patients that suffer from diseases correlated with iron homeostasis like Iron Deficiency (ICD 10 code D50) or Hereditary Haemochromatosis (HHC, ICD 10 code E83.1).

MnCl2:

Due to a delay in the correspondance between the registrant of this test substance and the Manganese Consortium, no first hand animal data is available.

In the DRAFT TOXICOLOGICAL PROFILE FOR MANGANESE, 2008, by the Agency for Toxic Substances and Disease Registry an interim guidance value of 0.16 mg manganese/kg/day is reported. The value is based on the Tolerable Upper Intake Level for 70 kg adults of 11 mg manganese/day, established by the U.S. Food and Nutrition Board/Institute of Medicine.

 

AlCl3:

For AlCl3 Beekhuijzen 2007 is the key study. In a combined repeated dose / reproductive screening study (OECD 422), administration of Aluminium chloride basic by oral gavage to male and female rats at dose levels of 20, 200 or 1000 mg /kg/d (equivalent to 3.6, 18 and 90 mg/kg bw/d) was studied. As chloride, hydroxide and sulfate are anions that are essential for cellular life and are found in living cells in high abundance their effect on toxicity is regarded negligible. In addition basic aluminium chloride will be transferred into aluminium chloride when passing the stomach. Therefore results for this test item can be read across to aluminium trichloride (AlCl3). No toxic effects were observed in females at any dose. Therefore, the overall NOAEL for female rats was established to be 1000 mg/kg bw/day (equivalent to 90 mg/kg bw/d Al(III)). For males the NOAEL for local effects was established to be 200 mg/kg bw/day (equivalent to 18 mg/kg bw/d Al(III) = 88.96 mg/kg bw AlCl3) and for systemic toxicity 1000 mg/kg bw/day (equivalent to 90 mg/kg bw/d Al(III)).

In addition a study using aluminium citrate was conducted to analyse the effect of aluminium on neurotoxicity in the offspring after oral dosing in a developmental neurotoxicity study. See Semple 2010 in chapter 7.9.1. A NOAEL of 30 mg/Kg bw Al(III) (= 148.27 mg/kg bw/d AlCl3) was determined based on effects in fore- and hind-limb grip strength and other parameters. Nevertheless this finding is of less relevance as the complexation with citrate increases the aluminium uptake as compared to aluminium chloride.

 

HCl:

 

- dermal:

FeCl2:

No data is available.

 

MnCl2:

No data is available.

 

AlCl3:

No data is available.

 

HCl:

No data is available.

 

- inhalation:

FeCl2:

No data is available.

 

MnCl2:

Due to a delay in the correspondance between the registrant of this test substance and the Manganese Consortium, no first hand animal data is available.

Secondary data from the ACGIH document "Manganese, Elemental and Inorganic Compounds: TLV® Chemical Substances Draft Documentation, Notice of Intended Change" reports a TLV–TWA of 0.02 mg Mn/m³ for respirable particulate matter and a TLV–TWA of 0.2 mg Mn/m 3 for inhalable particulate matter (= 0.0458 and 0.458 mg MnCl2/m3).

Critical endpoints are preclinical, adverse, neurophysiological, and neuropsychological effects.

 

AlCl3:

Weigand 1973 is the key study for AlCl3. The effects of 90-day exposure of rats to deodorant spray containing 9% aluminiumhydroxychloride was tested in this inhalation study. 10 male and 10 female rats were exposed, while another 10 males and females formed the control group. Clinical signs, body weights, blood and urine and macro and microscopic abnormalities were recorded. One male rat died after 62 days of inhalation without clear symptoms. No adverse effects were observed on body weight, blood and urine, as well as albumine/globuline in blood and enzymeactivities. Organ weights were also normal. Macro and microscopic examination showed moderate phagocytose in the lungs and small dust spread into lymph peribronchial lymph nodes in all animals. A LOAEC of 15.3 mg/m3 (= 17.76 mg/m3 AlCl3 = 3.59 mg/m³ Al) was derived.

In Steinhagen 1978 groups of rats and guinea pigs were exposed, by inhalation, to 0.25, 2.5 and 25 mg/m3 of aluminium chlorhydrate (ACH) for six months to study the effects of a common comoponent of antipersiparants. Similar groups of animals of both species exposed to clean air served as controls. The ACH was generated as a particulate dust using a Wright dust feed mechanism. After six months of exposure, animals were sacrificed. Decreases in body weight were seen in rats exposed to 25 mg/m3 of ACH. Marked increases in lung weights and significant increases in lung to body weight ratios were seen in rats and guinea pigs exposed to 25 mg/m3 of ACH. The lungs of all rats and guinea pigs showed significant increases in aluminium accumulation when exposed to either 0.25, 2.5 or 25 mg/m3 of ACH. The lungs of all rats and guinea pigs exposed to either 2.5 or 25 mg/m3 of ACH contained exposure-related granulomatous reactions characterized by giant vacuoled macrophages containing basophilic material in association with eosinophilic cellular debris.

Under the conditions of this study, exposure-related changes were observed at all three dose levels. Therefore, a No Observed Adverse Effect Concentration (NOAEC) of 2.5 mg/m³ could be established.

As chloride, hydroxide and sulfate are anions that are essential for cellular life and are found in living cells in high abundance their effect on toxicity is regarded negligible therefore results for the above stated test items can be read across to aluminium trichloride. (AlCl3). Given a molecular weight of 96.449 g/mol for ACH and 133.34 g/mol for AlCl3 the NOAEC for AlCl3 can be can calculated as 3.54 mg/m³ (= 0.77 mg/m³ Al).

 

HCl:

Dudek 1984 (according to OECD 413 and GLP) is fully reliable and is the key study for HCl. Daily exposure of rats to gaseous hydrogen chloride at concentrations of 10, 20 and 50 ppm, 6 hours a day, 5 days per week up to a 90 day exposure period affected the body weight of males of one of the strains of rats at the highest dose level. Clinical signs observed were mainly related to the irritant/corrosive properties of HCl crusty nose, red or yellow/brown stained fur, poor quality coat, crusty eye(s) and nasal discharge in rats. No exposure-related changes were seen in haematology or clinical chemistry parameters or urinalysis, and no peculiar gross observations were noted at necropsy. Decreased liver weights and increases in other organs were recorded, but these changes were considered to be mainly related to the effect of treatment on general growth of the affected animals rather than direct effects on the organs themselves. Histopathological examination after 90 days exposure revealed minimal to mild rhinitis in both strains of rats. 

Based on effects on body weight both strains of rats, the LOAEL is considered to be 50 ppm in rats.

Based on the lack of effects on body weight and the lack of pathological findings except for effects of site-of-contact local irritation, the NOAEC for repeated dose inhalation toxicity can be set at 20 ppm for rats (=30 mg/m³). The NOEL, at least for rats, can be set at 10 ppm.

In an additional study (Buckley 1984) groups of Swiss mice were exposed to hydrochloric acid at the RD50 (concentration which causes a 50% decrease in respiratory rate = 309 ppm) for three consecutive days, 6 hrs/day. Five histological sections of the head were prepared after decalcification and scored for severity of lesions. Trachea and lungs were also examined. Hydrochloric acid at 309 ppm is irritant for the upper respiratory tract of mice, causing death and severe pathological changes on the respiratory epithelium, with evidence of exfoliation, erosion, ulceration and necrosis, and only minimal inflammation. Minimal ulceration and necrosis were also observed on the olfactory epithelium. Serous exudate was present, but no lesions were detected on the lungs.

 

Justification for classification or non-classification

Not yet finally assessed as based on secondary source data

Based on the above stated results on oral repeated dose toxicity the test substance should be classified as STOT RE1 (H372: Causes damage to liver, brain and haematopoietic system through prolonged or repeated exposure via the oral or the dermal route) concerning oral or dermal exposure.

Based on the assessment of the repeated dose toxicity, stated above, the test substance would be classified as R48/24/25 (Danger of serious damage to health by prolonged exposure) according to Council Directive 2001/59/EC (28th ATP of Directive 67/548/EEC).

inhalation: not relevant as the liquid form does not produce inhalable particles.